The goal of this project is to explore the molecular mechanisms underlying the relationship between stress and alcohol's motivational and neuroadaptive consequences. We shall focus on the role of corticotropin-releasing hormone (CRH), the critical mediator of the stress response, in determining these alcohol effects. Relatively little is understood concerning alcohol consumption and relief from stress or the influence of stress hormones on alcohol reward neuroadaptation. Whereas there is substantial support for these associations, thus far there are no causal links. We postulate that CRH is a principle element, perhaps even the keystone, in stress-associated mechanisms of alcohol addiction, and that disruption or dysregulation of CRH pathways leading to altered stress reactivity thereby influences patterns of ethanol reinforcement, aversion and neuroadaption. We propose to test these postulates using mice with specific genetic alterations in CRH pathways. In particular, we will test mice deficient in CRH or the CRH receptors, CRH-R1 and CRH-R2 and mice that overexpress CRH in the brain. We predict that specific effects of these mutations will be seen on ethanol reinforcement, aversion, and neuroadaptation to ethanol. Specific aim 1 will determine whether dysregulation of CRH pathways alters the motivational effects of ethanol. We shall measure voluntary ethanol drinking behavior, and ethanol-induced conditioned place preference and taste aversion in the CRH mutant lines listed above. Specific aim 2 will determine whether dysregulation of CRH pathways alters neuroadaption to ethanol. We shall measure ethanol-induced sensitization and cross-sensitization between stress and ethanol, and severity of ethanol dependence. Specific aim 3 will determine whether specific changes in gene expression patterns are associated with behavioral patterns of neuroadaptation of ethanol. This research represents an important step toward the validation of CRH receptors as targets for future medications development in the treatment and prevention of alcoholism.